Deacetylase inhibitors

ABSTRACT

The present invention provides hydroxamate compounds which are deacetylase inhibitors. The compounds are suitable for pharmaceutical compositions having anti-proliferative properties.

The present invention relates to hydroxamate compounds which areinhibitors of histone deacetylase. The inventive compounds are useful aspharmaceuticals for the treatment of proliferative diseases.

BACKGROUND

Reversible acetylation of histones is a major regulator of geneexpression that acts by altering accessibility of transcription factorsto DNA. In normal cells, histone deacetylase (HDA) and histoneacetyltrasferase together control the level of acetylation of histonesto maintain a balance. Inhibition of HDA results in the accumulation ofhyperacetylated histones, which results in a variety of cellularresponses.

Inhibitors of HDA have been studied for their therapeutic effects oncancer cells. For example, butyric acid and its derivatives, includingsodium phenylbutyrate, have been reported to induce apoptosis in vitroin human colon carcinoma, leukemia and retinoblastoma cell lines.However, butyric acid and its derivatives are not useful pharmacologicalagents because they tend to be metabolized, rapidly and have a veryshort half-life in vivo. Other inhibitors of HDA that have Been widelystudied for their anti-cancer activities are trichostatin A andtrapoxin. Trichostatin A is an antifungal and antibiotic and is areversible inhibitor of mammalian HDA. Trapoxin is a cyclictetrapeptide, which is an irreversible inhibitor of mammalian HDA.Although trichostatin and trapoxin have been studied for theiranti-cancer activities, the in vivo instability of the compounds makesthem less suitable as anti-cancer drugs. There remains a need for anactive compound that is suitable for treating tumors, includingcancerous tumors, that is highly efficacious and stable.

SUMMARY

The present invention provides efficacious deacetylase inhibitorcompounds that are useful as pharmaceutical agents having the formula(I):

wherein

-   -   R₁ is H, halo, or a straight chain C₁-C₆ alkyl (especially        methyl, ethyl or n-propyl, which methyl, ethyl and n-propyl        substituents are unsubstituted or substituted by one or more        substituents described below for alkyl substituents);    -   R₂ is selected from H, C₁-C₁₀ alkyl, (e.g. methyl, ethyl or        —CH₂CH₂—OH), C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉        heterocycloalkylalkyl, cycloalkylalkyl (e.g.,        cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g. benzyl),        heteroarylalkyl (e.g. pyridylmethyl), —(CH₂)_(n)C(O)R₆,        —(CH₂)—OC(O)R₆, amino acyl, HON—C(O)CH═C(R₁)-aryl-alkyl- and        —(CH₂)_(n)R₇;    -   R₃ and R₄ are the same or different and independently H, C₁-C₆        alkyl, acyl or acylamino, or R₃ and R₄ together with the carbon        to which they are bound represent C═O, C═S, or C═NR₈, or R₂        together with the nitrogen to which it is bound and R₃ together        with the carbon to which it is bound can form a C₄-C₉        heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic        polyheterocycle, or a mixed aryl and non-aryl polyheterocycle        ring;    -   R₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl (e.g.        benzyl), heteroarylalkyl (e.g. pyridylmethyl), aromatic        polycycles, non-aromatic polycycles, mixed aryl and non-aryl        polycycles, polyheteroaryl, non-aromatic polyheterocycles, and        mixed aryl and non-aryl polyheterocycles; n, n₁, n₂ and n₃ are        the same or different and independently selected from 0-6, when        n, is 1-6, each carbon atom can be optionally and independently        substituted with R₃ and/or R₄;    -   X and Y are the same or different and independently selected        from H, halo, C₁-C₄ alkyl, such as CH₃ and CF₃, NO₂, C(O)R₁,        OR₉, SR₉, CN, and NR₁₀R₁₁;    -   R₆ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl),        aryl, heteroaryl, arylalkyl (e.g., benzyl, 2-phenylethenyl),        heteroarylalkyl (e.g., pyridylmethyl), OR₁₂, and NR₁₃R₁₄;    -   R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, and        NR₁₂SO₂R₆;    -   R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉        cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl        (e.g., benzyl), and heteroarylalkyl (e.g., pyridylmethyl);    -   R₉ is selected from C₁-C₄ alkyl, for example, CH₃ and CF₃,        C(O)-alkyl, for example O(O)CH₃, and C(O)CF₃;    -   R₁₀ and R₁₁ are the same or different and independently selected        from H, C₁-C₄ alkyl, and —C(O)-alkyl;    -   R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, aryl, mixed aryl        and non-aryl polycycle, heteroaryl, arylalkyl (e.g., benzyl),        and heteroarylalkyl (e.g., pyridylmethyl);    -   R₁₃ and R₁₄ are the same or different and independently selected        from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,        aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroarylalkyl        (e.g., pyridylmethyl), amino acyl, or R₁₃ and R₁₄ together with        the nitrogen to which they are bound are C₄-C₉ heterocycloalkyl,        heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or        mixed aryl and non-aryl polyheterocycle;    -   R₁₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl        and (CH₂)_(m)ZR₁₂;    -   R₁₆ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl,        heteroarylalkyl and (CH₂)_(m)ZR₁₂;    -   R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, aromatic polycycles, heteroaryl,        arylalkyl, heteroarylalkyl, polyheteroaryl and NR₁₃R₁₄;    -   m is an integer selected from 0 to 6; and    -   Z is selected from O, NR₁₃, S and S(O),        or a pharmaceutically acceptable salt thereof.

The compounds of the present invention are suitable as active agents inpharmaceutical compositions that are efficacious particularly fortreating cellular proliferative ailments. The pharmaceutical compositionhas a pharmaceutically effective amount of the present active agentalong with other pharmaceutically acceptable exicipients, carriers,fillers, diluents and the like. The term pharmacuetically effectiveamount as used herein indicates an amount necessary to administer to'ahost to achieve a therapeutic result, especially an anti-tumor effect,e.g., inhibition of proliferation of malignant cancer cells, benigntumor cells or other proliferative cells.

DETAILED DESCRIPTION

The present invention provides hydroxamate compounds, e.g., hydroxamicacids, that are inhibitors of deacetylases, preferably inhibitors ofhistone deacetylases. The hydroxamate compounds are highly suitable fortreating tumors, including cancerous tumors. The hydroxamate compoundsof the present invention have the following structure (I):

wherein

-   -   R₁ is H, halo, or a straight chain C₁-C₆ alkyl (especially        methyl, ethyl or n-propyl, which methyl, ethyl and n-propyl        substituents are unsubstituted or substituted by one or more        substituents described below for alkyl substituents);

R₂ is selected from H, C₁-C₁₀ alkyl, (preferably C₁-C₆ alkyl, e.g.methyl, ethyl or —CH₂CH₂—OH), C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,C₄-C₉ heterocycloalkylalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl),aryl, heteroaryl, arylalkyl (e.g. benzyl), heteroarylalkyl (e.g.pyridylmethyl), —(CH₂)_(n)C(O)R₆, —(CH₂)_(n)OC(O)R₆, amino acyl,HON—C(O)—CH═C(R₁)-aryl-alkyl- and —(CH₂)_(n)R₇;

R₃ and R₄ are the same or different and independently H, C₁-C₆ alkyl,acyl or acylamino, or R₃ and R₄ together with the carbon to which theyare bound represent C═O, C═S, or C═NR₈, or R₂ together with the nitrogento which it is bound and R₃ together with the carbon to which it isbound can form a C₄-C₉ heterocycloalkyl, a heteroaryl, a polyheteroaryl,a non-aromatic polyheterocycle, or a mixed aryl and non-arylpolyheterocycle ring;

-   -   R₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl (e.g.        benzyl), heteroarylalkyl (e.g. pyridylmethyl), aromatic        polycycles, non-aromatic polycycles, mixed aryl and non-aryl        polycycles, polyheteroaryl, non-aromatic polyheterocycles, and        mixed aryl and non-aryl polyheterocycles;    -   n, n₁, n₂ and n₃ are the same or different and independently        selected from 0-6, when n₁ is 1-6, each carbon atom can be        optionally and independently substituted with R₃ and/or R₄;    -   X and Y are the same or different and independently selected        from H, halo, C₁-C₄ alkyl, such as CH₃ and CF₃, NO₂, C(O)R₁,        OR₉, SR₉, CN, and NR₁₀R₁₁;    -   R₆ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl),        aryl, heteroaryl, arylalkyl (e.g., benzyl, 2-phenylethenyl),        heteroarylalkyl (e.g., pyridylmethyl), OR₁₂, and NR₁₃R₁₄;    -   R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, and        NR₁₂SO₂R₆;    -   R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉        cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl        (e.g., benzyl), and heteroarylalkyl (e.g., pyridylmethyl);    -   R₉ is selected from C₁-C₄ alkyl, for example, CH₃ and CF₃,        C(O)-alkyl, for example C(O)CH₃, and C(O)CF₃;    -   R₁₀ and R₁₁ are the same or different and independently selected        from H, C₁-C₄ alkyl, and —C(O)-alkyl;    -   R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, aryl, mixed aryl        and non-aryl polycycle, heteroaryl, arylalkyl (e.g., benzyl),        and heteroarylalkyl (e.g., pyridylmethyl);    -   R₁₃ and R₁₄ are the same or different and independently selected        from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,        aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroarylalkyl        (e.g., pyridylmethyl), amino acyl, or R₁₃ and R₁₄ together with        the nitrogen to which they are bound are C₄-C₉ heterocycloalkyl,        heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or        mixed aryl and non-aryl polyheterocycle;    -   R₁₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl        and (CH₂)_(m)ZR₁₂;    -   R₁₆ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl,        heteroarylalkyl and (CH₂)_(m)ZR₁₂;    -   R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, aromatic polycycles, heteroaryl,        arylalkyl, heteroarylalkyl, polyheteroaryl and NR₁₃R₁₄;    -   m is an integer selected from 0 to 6; and    -   Z is selected from O, NR₁₃, S and S(O),        or a pharmaceutically acceptable salt thereof.

As appropriate, unsubstituted means that there is no substituent or thatthe only substituents are hydrogen.

Halo substituents are selected from fluoro, chloro, bromo and iodo,preferably fluoro or chloro.

Alkyl substituents include straight and branched C₁-C₆alkyl, unlessotherwise noted. Examples of suitable straight and branched C₁-C₆alkylsubstituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl,sec-butyl, t-butyl, and the like. Unless otherwise noted, the alkylsubstituents include both unsubstituted alkyl groups and alkyl groupsthat are substituted by one or more suitable substituents, includingunsaturation (i.e. there are one or more double or triple C—C bonds),acyl, cycloalkyl, halo, oxyalkyl, alkylamino, aminoalkyl, acylamino andOR₁₅, for example, alkoxy. Preferred substituents for alkyl groupsinclude halo, hydroxy, alkoxy, oxyalkyl, alkylamino, and aminoalkyl.

Cycloalkyl substituents include C₃-C₉ cycloalkyl groups, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unlessotherwise specified. Unless otherwise noted, cycloalkyl substituentsinclude both unsubstituted cycloalkyl groups and cycloalkyl groups thatare substituted by one or more suitable substituents, including C₁-C₆alkyl, halo, hydroxy, aminoalkyl, oxyalkyl, alkylamino, and OR₁₅, suchas alkoxy. Preferred substituents for cycloalkyl groups include halo,hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.

The above discussion of alkyl and cycloalkyl substituents also appliesto the alkyl portions of other substituents, such as without limitation,alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl,alkylsulfonyl and alkyl ester substituents and the like.

Heterocycloalkyl substituents include 3 to 9 membered aliphatic rings,such as 4 to 7 membered aliphatic rings, containing from one to threeheteroatoms selected from nitrogen, sulfur, oxygen. Examples of suitableheterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl,tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl,morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and1,4-oxathiapane. Unless otherwise noted, the rings are unsubstituted orsubstuted on the carbon atoms by one or more suitable substituents,including C₁-C₆ alkyl, C₄-C₉ cycloalkyl, aryl, heteroaryl, arylalkyl(e.g., benzyl), and heteroarylalkyl (e.g., pyridylmethyl), halo, amino,alkyl amino and OR₁₅, for example alkoxy. Unless otherwise noted,nitrogen heteroatoms are unsubstituted or substituted by H, C₁-C₄ alkyl,arylalkyl (e.g., benzyl), and heteroarylalkyl (e.g., pyridylmethyl),acyl, aminoacyl, alkylsulfonyl, and arylsulfonyl.

Cycloalkylalkyl substituents include compounds of the formula—(CH₂)_(n5)-cycloalkyl wherein n5 is a number from 1-6. Suitablealkylcycloalkyl substituents include cyclopentylmethyl-,cyclopentylethyl, cyclohexylmethyl and the like. Such substituents areunsubstituted or substituted in the alkyl portion or in the cycloalkylportion by a suitable substituent, including those listed above foralkyl and cycloalkyl.

Aryl substituents include unsubstituted phenyl and phenyl substituted byone or more suitable substituents, including C₁-C₆ alkyl,cycloalkylalkyl (e.g., cyclopropylmethyl), O(CO)alkyl, oxyalkyl, halo,nitro, amino, alkylamino, aminoalkyl, alkyl ketones, nitrile,carboxyalkyl, alkylsulfonyl, aminosulfonyl, arylsulfonyl, and OR₁₅, suchas alkoxy. Preferred substituents include including C₁-C₆ alkyl,cycloalkyl (e.g., cyclopropylmethyl), alkoxy, oxyalkyl, halo, nitro,amino, alkylamino, aminoalkyl, alkyl ketones, nitrile, carboxyalkyl,alkylsulfonyl, arylsulfonyl, and aminosulfonyl. Examples of suitablearyl groups include C₁-C₄alkylphenyl, C₁-C₄alkoxyphenyl,trifluoromethylphenyl, methoxyphenyl, hydroxyethylphenyl,dimethylaminophenyl, aminopropylphenyl, carbethoxyphenyl,methanesulfonylphenyl and tolylsulfonylphenyl.

Aromatic polycycles include naphthyl, and naphthyl substituted by one ormore suitable substituents, including C₁-C₆ alkyl, alkylcycloalkyl(e.g., cyclopropylmethyl), oxyalkyl, halo, nitro, amino, alkylamino,aminoalkyl, alkyl ketones, nitrile, carboxyalkyl, alkylsulfonyl,arylsulfonyl, aminosulfonyl and OR₁₅, such as alkoxy.

Heteroaryl substituents include compounds with a 5 to 7 member aromaticring containing one or more heteroatoms, for example from 0.1 to 4heteroatoms, selected from N, O and S. Typical heteroaryl substituentsinclude furyl, thienyl, pyrrole, pyrazole, triazole, thiazole, oxazole,pyridine, pyrimidine, isoxazolyl, pyrazine and the like. Unlessotherwise noted, heteroaryl substituents are unsubstituted orsubstituted on a carbon atom by one or more suitable substituents,including alkyl, the alkyl substituents identified above, and anotherheteroaryl substituent. Nitrogen atoms are unsubstituted or substituted,for example by R₁₃; especially useful N substituents include H, C₁-C₄alkyl, acyl, aminoacyl, and sulfonyl.

Arylalkyl substituents include groups of the formula —(CH₂)_(n5)-aryl,—(CH₂)_(n5-1)-(CHaryl)-(CH₂)_(n5)-aryl or —(CH₂)_(n5-1)CH(aryl)(aryl)wherein aryl and n5 are defined above. Such arylalkyl substituentsinclude benzyl, 2-phenylethyl, 1-phenylethyl, tolyl-3-propyl,2-phenylpropyl, diphenylmethyl, 2-diphenylethyl,5,5-dimethyl-3-phenylpentyl and the like. Arylalkyl substituents areunsubstituted or substituted in the alkyl moiety or the aryl moiety orboth as described above for alkyl and aryl substituents.

Heteroarylalkyl substituents include groups of the formula—(CH₂)_(n5)-heteroaryl wherein heteroaryl and n5 are defined above andthe bridging group is linked to a carbon or a nitrogen of the heteroarylportion, such as 2-, 3- or 4-pyridylmethyl, imidazolylmethyl,quinolylethyl, and pyrrolylbutyl. Heteroaryl substituents areunsubstituted or substituted as discussed above for heteroaryl and alkylsubstituents.

Amino acyl substituents include groups of the formula—C(O)—(CH₂)_(n)—C(H)(NR₁₃R₁₄)—(CH₂)_(n)—R₅ wherein n, R₁₃, R₁₄ and R₅are described above. Suitable aminoacyl substituents include natural andnon-natural amino acids such as glycinyl, D-tryptophanyl, L-lysinyl, D-or L-homoserinyl, 4-aminobutryic acyl, ±-3-amin-4-hexenoyl.

Non-aromatic polycycle substituents include bicyclic and tricyclic fusedring systems where each ring can be 4-9 membered and each ring cancontain zero, 1 or more double and/or triple bonds. Suitable examples ofnon-aromatic polycycles include decalin, octahydroindene,perhydrobenzocycloheptene, perhydrobenzo-[1-azulene. Such substituentsare unsubstituted or substituted as described above for cycloalkylgroups.

Mixed aryl and non-aryl polycycle substituents include bicyclic andtricyclic fused ring systems where each ring can be 4-9 membered and atleast one ring is aromatic. Suitable examples of mixed aryl and non-arylpolycycles include methylenedioxyphenyl, bis-methylenedioxyphenyl,1,2,3,4-tetrahydronaphthalene, dibenzosuberane, dihdydroanthracene,9H-fluorene. Such substituents are unsubstituted or substituted by nitroor as described above for cycloalkyl groups.

Polyheteroaryl substituents include bicyclic and tricyclic fused ringsystems where each ring can independently be 5 or 6 membered and containone or more heteroatom, for example, 1, 2, 3, or 4 heteroatoms, chosenfrom O, N or S such that the fused ring system is aromatic. Suitableexamples of polyheteroaryl ring systems include quinoline, isoquinoline,pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran,benzothiofuran, benzindole, benzoxazole, pyrroloquinoline, and the like.Unless otherwise noted, polyheteroaryl substituents are unsubstituted orsubstituted on a carbon atom by one or more suitable substituents,including alkyl, the alkyl substituents identified above and asubstituent of the formula —O—(CH₂CH═CH(CH₃)(CH₂))₁₋₃H. Nitrogen atomsare unsubstituted or substituted, for example by R₁₃; especially usefulN substituents include H, C₁-C₄ alkyl, acyl, aminoacyl, and sulfonyl.

Non-aromatic polyheterocyclic substituents include bicyclic andtricyclic fused ring systems where each ring can be 4-9 membered,contain one or more heteroatom, for example, 1, 2, 3, or 4 heteroatoms,chosen from O, N or S and contain zero or one or more C—C double ortriple bonds. Suitable examples of non-aromatic polyheterocycles includehexitol, cis-perhydro-cyclohepta[b]pyridinyl,decahydro-benzo[f][1,4]oxazepinyl, 2,8-dioxabicyclo[3.3.0]octane,hexahydro-thieno[3,2-b]thiophene, perhydropyrrolo[3,2-b]pyrrole,perhydronaphthyridine, perhydro-1H-dicyclopenta[b,e]pyran. Unlessotherwise noted, non-aromatic polyheterocyclic substituents areunsubstituted or substituted on a carbon atom by one or moresubstituents, including alkyl and the alkyl substituents identifiedabove. Nitrogen atoms are unsubstituted or substituted, for example, byR₁₃; especially useful N substituents include H, C₁-C₄ alkyl, acyl,aminoacyl, and sulfonyl.

Mixed aryl and non-aryl polyheterocycles substituents include bicyclicand tricyclic fused ring systems where each ring can be 4-9 membered,contain one or more heteroatom chosen from O, N or S, and at least oneof the rings must be aromatic. Suitable examples of mixed aryl andnon-aryl polyheterocycles include 2,3-dihydroindole,1,2,3,4-tetrahydroquinoline, 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine,5H-dibenzo[b,e][1,4]diazepine,1,2-dihydropyrrolo[3,4-b][1,5]benzodiazepine,1,5-dihydro-pyrido[2,3-b][1,4]diazepin-4-one,1,2,3,4,6,11-hexahydro-benzo[b]pyrido[2,3-e][1,4]diazepin-5-one. Unlessotherwise noted, mixed aryl and non-aryl polyheterocyclic substituentsare unsubstituted or substituted on a carbon atom by one or moresuitable substituents, including, —N—OH, ═N—OH, alkyl and the alkylsubstituents identified above. Nitrogen atoms are unsubstituted orsubstituted, for example, by R₁₃; especially useful N substituentsinclude H, C₁-C₄ alkyl, acyl, aminoacyl, and sulfonyl.

Amino substituents include primary, secondary and tertiary amines and insalt form, quaternary amines. Examples of amino substituents includemono- and di-alkylamino, mono- and di-aryl amino, mono- and di-aryalkylamino, aryl-arylalkylamino, alkyl-arylamino, alkyl-arylalkylamino andthe like.

Sulfonyl substituents include alkylsulfonyl and arylsulfonyl, forexample methane sulfonyl, benzene sulfonyl, tosyl and the like.

Acyl substituents include groups of formula —C(O)—W, —OC(O)—W, —C(O)—O—Wor —C(O)NR₁₃R₁₄, where W is R₁₆, H or cycloalkylalkyl.

Acylamino substituents include substituents of the formula—N(R₁₂)C(O)—W, —N(R₂)C(O)—O—W, and —N(R₁₂)C(O)—NHOH and R₁₂ and W aredefined above.

The R₂ substituent HON—C(OYCH═C(R₁)-aryl-alkyl- is a group of theformula

Preferences for each of the substituents include the following:

-   -   R₁ is H, halo, or a straight chain C₁-C₄ alkyl;    -   R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl, and —(CH₂)_(n)R₇;    -   R₃ and R₄ are the same or different and independently selected        from H, and C₁-C₆ alkyl, or R₃ and R₄ together with the carbon        to which they are bound represent C═O, C═S, or C═NR₈;    -   R₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,        a aromatic polycycle, a non-aromatic polycycle, a mixed aryl and        non-aryl polycycle, polyheteroaryl, a non-aromatic        polyheterocycle, and a mixed aryl and non-aryl polyheterocycle;    -   n, n₁, n₂ and n₃ are the same or different and independently        selected from 0-6, when n, is 1-6, each carbon atom is        unsubstituted or independently substituted with R₃ and/or R₄;    -   X and Y are the same or different and independently selected        from H, halo, C₁-C₄ alkyl, CF₃, NO₂, C(O)R₁, OR₉, SR₉, CN, and        NR₁₀R₁₁;    -   R₆ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, OR₁₂, and NR₁₃R₁₄;    -   R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, and        NR₁₂SO₂R₆;    -   R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉        cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl,        and heteroarylalkyl;    -   R₉ is selected from C₁-C₄ alkyl and C(O)-alkyl;    -   R₁₀ and R₁₁ are the same or different and independently selected        from H, C₁-C₄ alkyl, and —C(O)-alkyl;    -   R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, arylalkyl, and        heteroarylalkyl;    -   R₁₃ and R₁₄ are the same or different and independently selected        from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,        aryl, heteroaryl, arylalkyl, heteroarylalkyl and amino acyl;    -   R₁₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl        and (CH₂)_(m)ZR₁₂;    -   R₁₆ is selected from C₁-C₈ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl        and (CH₂)_(m)ZR₁₂;

-   R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉    heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and    NR₁₃R₁₄;    -   m is an integer selected from 0 to 6; and    -   Z is selected from O, NR₁₃, S, S(O),        or a pharmaceutically acceptable salt thereof.

Useful compounds of the formula (I) include those wherein each of R₁, X,Y, R₃, and R₄ is H, including those wherein one of n₂ and n₃ is zero andthe other is 1, especially those wherein R₂ is H or —CH₂—CH₂—OH.

One suitable genus of hydroxamate compounds are those of formula Ia:

wherein

-   -   n₄ is 0-3,    -   R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and —(CH₂)_(n)R₇;    -   R₅′ is heteroaryl, heteroarylalkyl (e.g., pyridylmethyl),        aromatic polycycles, non-aromatic polycycles, mixed aryl and        non-aryl polycycles, polyheteroaryl, or mixed aryl and non-aryl        polyheterocycles,        or a pharmaceutically acceptable salt thereof.

Another suitable genus of hydroxamate compounds are those of formula Ia:

wherein

-   -   n₄ is 0-3,    -   R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and —(CH₂)_(n)R₇;    -   R₅′ is aryl, arylalkyl, aromatic polycycles, non-aromatic        polycycles, and mixed aryl and non-aryl polycycles; especially        aryl, such as p-fluorophenyl, p-chlorophenyl,        p-O—C₁-C₄-alkylphenyl, such as p-methoxyphenyl, and        p-C₁-C₄-alkylphenyl; and arylalkyl, such as benzyl, ortho, meta        or para-fluorobenzyl, ortho, meta or para-chlorobenzyl, ortho,        meta or para-mono, di or tri-O—C₁-C₄-alkylbenzyl, such as ortho,        meta or para-methoxybenzyl, m,p-diethoxybenzyl,        o,m,p-triimethoxybenzyl, and ortho, meta or para- mono, di or        tri C₁-C₄-alkylphenyl, such as p-methyl, m,m-diethylphenyl,        or a pharmaceutically acceptable salt thereof.

Another interesting genus are the compounds of formula Ib:

wherein

-   -   R₂′ is selected from H, C₁-C₆ alkyl, C₄-C₆ cycloalkyl,        cycloalkylalkyl (e.g., cyclopropylmethyl), (CH₂)₂₋₄OR₂₁ where        R₂₁ is H, methyl, ethyl, propyl, and i-propyl, and    -   R₅″ is unsubstituted 1H-indol-3-yl, benzofuran-3-yl or        quinolin-3-yl, or substituted 1H-indol-3-yl, such as        5-fluoro-1H-indol-3-yl or 5-methoxy-1H-indol-3-yl,        benzofuran-3-yl or quinolin-3-yl,        or a pharmaceutically acceptable salt thereof.

Another interesting genus of hydroxamate compounds are the compounds offormula (Ic)

wherein

-   -   the ring containing Z, is aromatic or non-aromatic, which        non-aromatic rings are saturated or unsaturated,    -   Z₁ is O, S or N—R₂₀,    -   R18 is H, halo, C₁-C₆alkyl (methyl, ethyl, t-butyl),        C₃-C₇cycloalkyl, aryl, for example unsubstituted phenyl or        phenyl substituted by 4-OCH₃ or 4-CF₃, or heteroaryl, such as        2-furanyl, 2-thiophenyl or 2-, 3- or 4-pyridyl;    -   R₂₀ is H, C₁-C₆alkyl, C₁-C₆alkyl-C₃-C₉cycloalkyl (e.g.,        cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g., benzyl),        heteroarylalkyl (e.g., pyridylmethyl), acyl (acetyl, propionyl,        benzoyl) or sulfonyl (methanesulfonyl, ethanesulfonyl,        benzenesulfonyl, toluenesulfonyl)    -   A₁ is 1, 2 or 3 substituents which are independently H,        C₁-C₆alkyl, —OR₁₉, halo, alkylamino, aminoalkyl, halo, or        heteroarylalkyl (e.g., pyridylmethyl),    -   R₁₉ is selected from H, C₁-C₆alkyl, C₄-C₉cycloalkyl,        C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g.,        benzyl), heteroarylalkyl (e.g., pyridylmethyl) and        —(CH₂CH═CH(CH₃)(CH₂))₁₋₃H;

R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and —(CH₂)_(n)R₇;

-   -   v is 0, 1 or 2,    -   p is 0-3, and    -   q is 1-5 and r is 0 or    -   q is 0 and r is 1-5,        or a pharmaceutically acceptable salt thereof. The other        variable substituents are as defined above.

Especially useful compounds of formula (Ic) are those wherein R₂ is H,or —(CH₂)_(p)CH₂OH, wherein p is 1-3, especially those wherein R₁ is H;such as those wherein R₁ is H and X and Y are each H, and wherein q is1-3 and r is 0 or wherein q is 0 and r is 1-3, especially those whereinZ₁ is N—R₂₀. Among these compounds R₂ is preferably H or —CH₂—CH₂—OH andthe sum of q and r is preferably 1.

Another interesting genus of hydroxamate compounds are the compounds offormula (Id)

whereinZ₁ is O, S or N—R₂₀,R₁₈ is H, halo, C₁-C₈alkyl (methyl, ethyl, t-butyl), C₃-C₇cycloalkyl,aryl, for example, unsubstituted phenyl or phenyl substituted by 4-OCH₃or 4-CF₃, or heteroaryl,R₂₀ is H, C₁-C₆alkyl, C₁-C₆alkyl-C₃-C₉cycloalkyl (e.g.,cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g., benzyl),heteroarylalkyl (e.g., pyridylmethyl), acyl (acetyl, propionyl, benzoyl)or sulfonyl (methanesulfonyl, ethanesulfonyl, benzenesulfonyl,toluenesulfonyl),A₁ is 1, 2 or 3 substituents which are independently H, C₁-C-₆alkyl,—OR₁₉, or halo,R₁₉ is selected from H, C₁-C₆alkyl, C₄-C₉cycloalkyl,C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), andheteroarylalkyl (e.g., pyridylmethyl);.p is 0-3, andq is 1-5 and r is 0 orq is 0 and r is 1-5,or a pharmaceutically acceptable salt thereof. The other variablesubstituents are as defined above.

Especially useful compounds of formula (Id) are those wherein R₂ is H,or —(CH₂)_(p)CH₂OH, wherein p is 1-3, especially those wherein R₁ is H;such as those wherein R₁ is H and X and Y are each H, and wherein 4 is1-3 and r is 0 or wherein q is 0 and r is 1-3. Among these compounds R₂is preferably H or —CH₂—CH₂—OH and the sum of q and r is preferably 1.

The present invention further relates to compounds of the formula (Ie)

or a pharmaceutically acceptable salt thereof. The variable substituentsare as defined above.

Especially useful compounds of formula (Ie) are those wherein R₁₈ is H,fluoro, chloro, bromo, a C₁-C₄alkyl group, a substituted C₁-C₄alkylgroup, a C₃-C₇cycloalkyl group, unsubstituted phenyl, phenyl substitutedin the para position, or a heteroaryl (e.g., pyridyl) ring.

Another group of useful compounds of formula (Ie) are those wherein R₂is H, or —(CH₂)_(p)CH₂OH, wherein p is 1-3, especially those wherein R₁is H; such as those wherein R₁ is H and of and Y are each H, and whereinq is 1-3 and r is 0 or wherein q is 0 and r is 1-3. Among thesecompounds R₂ is preferably H or —CH₂—CH₂—OH and the sum of q and r ispreferably 1.

Another group of useful compounds of formula (Ie) are those wherein R₁₈is H, methyl, ethyl, t-butyl, trifluoromethyl, cyclohexyl, phenyl,4-methoxyphenyl, 4-trifluoromethylphenyl, 2-furanyl, 2-thiophenyl, or2-, 3- or 4-pyridyl wherein the 2-furanyl, 2-thiophenyl and 2-, 3- or4-pyridyl substituents are unsubstituted or substituted as describedabove for heteroaryl rings; R₂ is H, or —(CH₂)_(p)CH₂OH, wherein p is1-3; especially those wherein R₁ is H and X and Y are each H, andwherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3. Among thesecompounds R₂ is preferably H or —CH₂—CH₂—OH and the sum of q and r ispreferably 1.

Those compounds of formula Ie wherein R₂₀ is H, or C₁-C₆alkyl,especially H, are important members of each of the subgenuses ofcompounds of formula Ie described above.

N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideandN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, are important compoundsof formula (Ie).

The present invention further relates to the compounds of the formula(If):

or a pharmaceutically acceptable salt thereof. The variable substituentsare as defined above.

Useful compounds of formula (If) are include those wherein R₂ is H, or—(CH₂)_(p)CH₂OH, wherein p is 1-3, especially those wherein R₁ is H;such as those wherein R₁ is H and X and Y are each H, and wherein q is1-3 and r is 0 or wherein q is 0 and r is 1-3. Among these compounds R₂is preferably H or —CH—CH₂—OH and the sum of q and r is preferably 1.

N-hydroxy-3-[4-[[[2-(benzofur-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, is an important compoundof formula (If).

The compounds described above are often used in the form of apharmaceutically acceptable salt. Pharmaceutically acceptable saltsinclude, when appropriate, pharmaceutically acceptable base additionsalts and acid addition salts, for example, metal salts, such as alkaliand alkaline earth metal salts, ammonium salts, organic amine additionsalts, and amino acid addition salts, and sulfonate salts. Acid additionsalts include inorganic acid addition salts such as hydrochloride,sulfate and phosphate, and organic acid addition salts such as alkylsulfonate, arylsulfonate, acetate, maleate, fumarate, tartrate, citrateand lactate. Examples of metal salts are alkali metal salts, such aslithium salt, sodium salt and potassium salt, alkaline earth metal saltssuch as magnesium salt and calcium salt, aluminum salt, and zinc salt.Examples of ammonium salts are ammonium salt and tetramethylammoniumsalt. Examples of organic amine addition salts are salts with morpholineand piperidine. Examples of amino acid addition salts are salts withglycine, phenylalanine, glutamic acid and lysine. Sulfonate saltsinclude mesylate, tosylate and benzene sulfonic acid salts.

As is evident to those skilled in the art, the many of the deacetylaseinhibitor compounds of the present invention contain asymmetric carbonatoms. It should be understood, therefore, that the individualstereoisomers are contemplated as being included within the scope ofthis invention.

The hydroxamate compounds of the present invention can be produced byknown organic synthesis methods. For example, the hydroxamate compoundscan be produced by reacting methyl 4-formyl cinnamate with tryptamineand then converting the reactant to the hydroxamate compounds. As anexample, methyl 4-formyl cinnamate 2, is prepared by acid catalyzedesterification of 4-formylcinnamic acid 3 (Bull. Chem. Soc. Jpn. 1995;68:2355-2362). An alternate preparation of methyl 4-formyl cinnamate 2is by a Pd-catalyzed coupling of methyl acrylate 4 with4-bromobenzaldehyde 5.

Additional starting materials can be prepared from 4-carboxybenzaldehyde6, and an exemplary method is illustrated for the preparation ofaldehyde 9, shown below. The carboxylic acid in 4-carboxybenzaldehyde 6can be protected as a silyl ester (e.g., the t-butyidimethylsilyl ester)by treatment with a silyl chloride (e.g., t-butyldimethylsilyl chloride)and a base (e.g. triethylamine) in an appropriate solvent (e.g.,dichloromethane). The resulting silyl ester 7 can undergo an olefinationreaction (e.g., a Horner-Emmons olefination) with a phosphonate ester(e.g., triethyl 2-phosphonopropionate) in the presence of a base (e.g.,sodium hydride) in an appropriate solvent (e.g., tetrahydrofuran (THF)).Treatment of the resulting diester with acid (e.g., aqueous hydrochloricacid) results in the hydrolysis of the silyl ester providing acid 8.Selective reduction of the carboxylic acid of 8 using, for example,borane-dimethylsuflide complex in a solvent (e.g., THF) provides anintermediate alcohol. This intermediate alcohol could be oxidized toaldehyde 9 by a number of known methods, including, but not limited to,Swern oxidation, Dess-Martin periodinane oxidation, Moffatt oxidationand the like.

The aldehyde starting materials 2 or 9 can be reductively aminated toprovide secondary or tertiary amines. This is illustrated by thereaction of methyl 4-formyl cinnamate 2 with tryptamine 10 using sodiumtriacetoxyborohydride (NaBH(OAc)₃) as the reducing agent indichloroethane (DCE) as solvent to provide amine 11. Other reducingagents can be used, e.g., sodium borohydride (NaBH₄) and sodiumcyanoborohydride (NaBH₃CN), in other solvents or solvent mixtures in thepresence or absence of acid catatylysts (e.g., acetic acid andtrifluoroacetic acid). Amine 11 can be converted directly to hydroxamicacid 12 by treatment with 50% aqueous hydroxylamine in a suitablesolvent (e.g., THF in the presence of a base, e.g., NaOH). Other methodsof hydroxamate formation are known and include reaction of an ester withhydroxylamine hydrochloride and a base (e.g., sodium hydroxide or sodiummethoxide) in a suitable solvent or solvent mixture (e.g., methanol,ethanol or methanol/THF).

Aldehyde 2 can be reductively aminated with a variety of amines,exemplified by, but not limited to, those illustrated in Table 1. Theresulting esters can be converted to target hydroxamates by the methodslisted. TABLE 1

Reducing Hydroxamate Amine Conditions Conditions R

NaBH(OAc)₃HOAc, DCE 2 M HONH₂ in MeOH

″ ″

″ ″

″ ″

″ ″

″ ″

″ ″

″ ″

″ ″

Ph(CH₂)₃NH₂ NaBH₃CN/MeOH/HOAc Ph(CH₂)₃

An alternate synthesis of the compounds of this invention starts byreductive amination of 4-formyl cinnamic acid 3, illustrated below with3-phenylpropylamine 13, using, for example, NaBH₃CN as the reducingagent in MeOH and HOAc as a catalyst. The basic nitrogen of theresulting amino acid 14 can be protected, for example, ast-butoxycarbamate (BOC) by reaction with di-t-butyldicarbonate to give15.

The carboxylic acid can be coupled with a protected hydroxylamine (e.g.,O-trityl hydroxylamine) using a dehydrating agent (e.g.,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl)) anda catalyst (e.g., 1-hydroxybenzotriazole hydrate (HOBT)) in a suitablesolvent (e.g., DMF) to produce 16. Treatment of 16 with a strong acid(e.g., trifluoroacetic acid (TFA)) provides a hydroxamic acid 17 of thepresent invention. Additional examples of compounds that can be preparedby this method are:

Tertiary amine compounds can be prepared by a number of methods.Reductive amination of 30 with nicotinaldehyde 32 using NaBH₃CN as thereducing agent in dichloroethane and HOAc as a catalyst provides ester34. Other reducing agents can be used (e.g., NaBH₄ and NaBH(OAc)₃) inother solvents or solvent mixtures in the presence or absence of acidcatalysts (e.g., acetic acid, trifluoroacetic acid and the like).Reaction of ester 34 with HONH₂.HCl, NaOH in MeOH provides hydroxamate36.

Tertiary amine compounds prepared by this methodology are exemplified,but not limited to, those listed in Table 2. TABLE 2

or

Hydroxamate Reducing Conditions Conditions

NaBH(OAc)₃ HOAc, DCE HONH₂.HCl/NaOMe/MeOH

NaBH(OAc)₃ HOAc, DCE HONH₂.HCl/NaOMe/MeOH

NaBH(OAc)₃ HOAc, DCE 2 M HONH₂ in MeOH

NaBH₃CN/MeOH/HOAc 2 M HONH₂ in MeOH

NaBH(OAc)₃ HOAc, DCE 2 M HONH₂ in MeOH

An alternate method for preparing tertiary amines is by reacting asecondary amine with an alkylating agent in a suitable solvent in thepresence of a base. For example, heating a dimethylsulfoxide (DMSO)solution of amine 11 and bromide 40 in the presence of (i-Pr)₂NEtyielded tertiary amine 42. Reaction of the tertiary amine 42 withHONH₂.HCl, NaOH in MeOH provides hydroxamate 43. The silyl group can beremoved by any method known to those skilled in the art. For example,the hydroxamate 43 can be treated with an acid, e.g., trifluoroaceticacid, or fluoride to produce hydroxyethyl compound 44.

The hydroxamate compound, or salt thereof, is suitable for preparingpharmaceutical compositions, especially pharmaceutical compositionshaving deacetylase, especially histone deacetylase, inhibitingproperties. Studies with athymic mice demonstrate that the hydroxamatecompound causes HDA inhibition and increased histone acetylation invivo, which triggers changes in gene expression that correlate withtumor growth inhibition.

The present invention further includes pharmaceutical compositionscomprising a pharmaceutically effective amount of one or more of theabove-described compounds as active ingredient. Pharmaceuticalcompositions according to the invention are suitable for enteral, suchas oral or rectal, and parenteral administration to mammals, includingman, for the treatment of tumors, alone or in combination with one ormore pharmaceutically acceptable carriers.

The hydroxamate compound is useful in the manufacture of pharmaceuticalcompositions having an effective amount the compound in conjunction oradmixture with excipients or carriers suitable for either enteral orparenteral application. Preferred are tablets and gelatin capsulescomprising the active ingredient together with (a) diluents; (b)lubricants, (c) binders (tablets); if desired, (d) disintegrants; and/or(e) absorbents, colorants, flavors and sweeteners. Injectablecompositions are preferably aqueous isotonic solutions or suspensions,and suppositories are advantageously prepared from fatty emulsions orsuspensions. The compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, the compositions may also contain othertherapeutically valuable substances. The compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain preferably about 1 to 50% of the activeingredient.

Suitable formulations also include formulations for parenteraladministration include aqueous and non-aqueous sterile injectionsolutions which may contain antioxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Theformulations may be presented in unit-dose or multi-dose containers, forexample, sealed ampules and vials, and may be stored in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, water for injections, immediately prior touse. Extemporaneous injection solutions and suspensions may be preparedfrom sterile powders, granules and tablets of the kind previouslydescribed.

As discussed above, the compounds of the present invention are usefulfor treating proliferative diseases. A proliferative disease is mainly atumor disease (or cancer) (and/or any metastases). The inventivecompounds are particularly useful for treating a tumor which is a breastcancer, genitourinary cancer, lung cancer, gastrointestinal cancer,epidermoid cancer, melanoma, ovarian cancer, pancreas cancer,neuroblastoma, head and/or neck cancer or bladder cancer, or in abroader sense renal, brain or gastric cancer; in particular (i) a breasttumor; an epidermoid tumor, such as an epidermoid head and/or neck tumoror a mouth tumor; a lung tumor, for example a small cell or non-smallcell lung tumor; a gastrointestinal tumor, for example, a colorectaltumor; or a genitourinary tumor, for example, a prostate tumor(especially a hormone-refractory prostate tumor); or (ii) aproliferative disease that is refractory to the treatment with otherchemotherapeutics; or (iii) a tumor that is refractory to treatment withother chemotherapeutics due to multidrug resistance.

In a broader sense of the invention, a proliferative disease mayfurthermore be a hyperproliferative condition such as leukemias,hyperplasias, fibrosis (especially pulmonary, but also other types offibrosis, such as renal fibrosis), angiogenesis, psoriasis,atherosclerosis and smooth muscle proliferation in the blood vessels,such as stenosis or restenosis following angioplasty.

Where a tumor, a tumor disease, a carcinoma or a cancer are mentioned,also metastasis in the original organ or tissue and/or in any otherlocation are implied alternatively or in addition, whatever the locationof the tumor and/or metastasis.

The compound is selectively toxic or more toxic to rapidly propiferatingcells than to normal cells, particularly in human cancer cells, e.g.,cancerous tumors, the compound has significant antiproliferative effectsand promotes differentiation, e.g., cell cycle arrest and apoptosis. Inaddition, the hydroxamate compound induces p21, cyclin-CDK interactingprotein, which induces either apoptosis or G1 arrest in a variety ofcell lines.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereto.

EXAMPLE P1 Preparation ofN-Hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide

4-formylcinnamic acid methylester is produced by adding 4-formylcinnamicacid (25 g, 0.143 mol) in MeOH and HCl (6.7 g, 0.18 mol). The resultingsuspension is heated to reflux for 3 hours, cooled and evaporated todryness. The resulting yellow solid is dissolved in EtOAc, the solutionwashed with saturated NaHCO₃, dried (MgSO₄) and evaporated to give apale yellow solid which is used without further purification (25.0 g,92%). To a solution of tryptamine (16.3 g, 100 mmol) and4-formylcinnamic acid methylester (19 g, 100 mmol) in dichloroethane,NaBH(OAc)₃ (21 g, 1.00 mmol) is added. After 4 hours the mixture isdiluted with 10% K₂CO₃ solution, the organic phase separated and theaqueous solution extracted with CH₂Cl₂. The combined organic extractsare dried (Na₂SO₄), evaporated and the residue purified by flashchromatography to produce3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoicacid methyl ester (29 g). A solution of KOH (12.9 g 87%, 0.2 mol) inMeOH (100 mL) is added to a solution of HONH₂.HCl (13.9 g, 0.2 mol) inMeOH (200 mL) and a precipitate results. After 15 minutes the mixture isfiltered, the filter cake washed with MeOH and the filtrate evaporatedunder vacuum to approximately 75 mL. The mixture is filtered and thevolume adjusted to 100 mL with MeOH. The resulting solution 2M HONH₂ isstored under N₂ at −20° C. for up to 2 weeks. Then3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoicacid methyl ester (2.20 g, 6.50 mmol) is added to 2 M HONH₂ in MeOH (30mL, 60 mmol) followed by a solution of KOH (420 mg, 6.5 mmol) in MeOH (5mL). After 2 hours dry ice is added to the reaction and the mixture isevaporated to dryness. The residue is dissolved in hot MeOH (20 mL),cooled and stored at −20° C. overnight. The resulting suspension isfiltered, the solids washed with ice cold MeOH and dried under vacuum,producingN-Hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(m/z 336 [MH⁺]).

EXAMPLE P2 Preparation ofN-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide

A solution of3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoicacid methyl ester (12.6 g, 37.7 mmol),(2-bromoethoxy)-tert-butyldimethylsilane (12.8 g, 53.6 mmol),(i-Pr)₂NEt, (7.42 g, 57.4 mmol) in DMSO (100 mL) is heated to 50° C.After 8 hours the mixture is partitioned with CH₂Cl₂/H₂O. The organiclayer is dried (Na₂SO₄) and evaporated. The residue is chromatographedon silica gel to produce3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoicacid methyl ester (13.1 g). Following the procedure described for thepreparation of the hydroxamate compound in Example. P1,3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoicacid methyl ester (5.4 g, 11 mmol) is converted toN-hydroxy-3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenamide(5.1 g,) and used without further purification. The hydroxamic acid (5.0g, 13.3 mmol) is then dissolved in 95% TFA/H₂O (59 mL) and heated to40-50° C. for 4 hours. The mixture is evaporated and the residuepurified by reverse phase HPLC to produceN-Hydroxy-3-[4-4[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamideas the trifluoroacetate salt (m/z 380 [MH⁺]).

EXAMPLE P3 Preparation ofN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide

A suspension of LiAlH₄ (17 g, 445 mmol) in dry THF (1000 mL) is cooledto 0° C. and 2-methylindole-3-glyoxylamide (30 g, 148 mmol) is added inportions over 30 min. The mixture is stirred at room temperature for 30min. and then maintained at reflux for 3 h. The reaction is cooled to 0°C. and treated with H₂O (17 ml), 15% NaOH (aq., 17 ml) and H₂O (51 ml).The mixture is treated with MgSO₄, filtered and the filtrate evaporatedto give 2-methyltryptamine which is dissolved in MeOH. Methyl4-formylcinnamate (16.9 g, 88.8 mmol) is added to the solution, followedby NaBH₃CN (8.4 g) and AcOH (1 equiv.). After 1 h the reaction isdiluted with NaHCO₃ (aq.) and extracted with EtOAc. The organic extractsare dried (MgSO₄), filtered and evaporated. The residue is purified bychromatography to give3-(4-[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl)phenyl)-(2E)-2-propenoicacid methyl ester. The ester is dissolved in MeOH, 1.0 M HCl/dioxane(1-1.5 eqiv.) is added followed by Et₂O. The resulting precipitate isfiltered and the solid washed with Et₂O and dried thoroughly to give3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoicacid methyl ester hydrochloride. 1.0 M NaOH (aq., 85 mL) is added to anice cold solution of the methyl ester hydrochloride (14.9 g, 38.6 mmol)and HONH₂ (50% aq. solution, 24.0 mL, ca. 391.2 mmol). After 6 h, theice cold solution is diluted with H₂O and NH₄Cl (aq., 0.86 M, 100 mL).The resulting precipitate is filtered, washed with H₂O and dried toaffordN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(m/z 350 [MH^(+]).)

EXAMPLES 1-265

The following compounds are prepared by methods analogous to thosedisclosed in Examples P1, P2 and P3: Example STRUCTURE m/z (MH⁺) 1

426 2

3

4

325 5

6

7

8

465 9

10

11

12

420 13

420 14

15

465 16

385 17

550 18

432 19

366 20

350 21

22

442 23

338 24

464 25

541 26

27

28

417 29

30

31

380 32

436 33

34

493 35

477 36

586 37

513 38

378 39

408 40

449 41

438 42

452 43

507 44

565 45

46

47

48

49

50

51

470 52

53

548 54

623 55

456 56

478 57

394 58

422 59

479 60

603 61

477 62

539 63

523 64

65

66

67

68

539 69

495 70

71

379 72

478 73

462 74

378 75

76

493 77

503 78

350 79

549 80

471 81

350 82

418 83

486 84

524 85

424 86

364 87

440 88

420 89

390 90

91

92

484 93

498 94

490 95

96

475 97

525 98

422 99

528 100

448 101

437 102

451 103

505 104

519 105

514 106

507 107

626 108

499 109

110

111

429 112

464 113

432 114

422 115

390 116

501 117

484 118

119

587 120

602 121

539 122

123

528 124

487 125

126

556 127

128

129

552 130

519 131

450 132

464 133

558 134

533 135

136

527 137

381 138

364 139

140

448 141

558 142

143

427 144

145

432 146

384 147

354 148

149

150

151

152

153

154

350 155

366 156

408 157

322 158

364 159

364 160

378 161

350 162

463 163

164

381 165

463 166

476 167

168

169

170

368 171

493 172

527 173

515 174

323 175

540 176

441 177

276 178

179

455 180

181

336 182

347 183

447 184

185

420 186

424 187

422 188

189

398 190

418 191

350 192

193

352 194

499 195

408 196

394 197

499 198

199

200

350 201

202

203

204

365 205

465 206

207

410 208

410 209

210

366 211

352 212

213

368 214

338 215

356 216

408 217

368 218

396 219

220

342 221

392 222

412 223

337 224

337 225

456 226

364 227

481 228

355 229

312 230

424 231

232

351 233

392 234

235

236

322 237

238

366 239

240

368 241

242

406 243

398 244

442 245

350 246

364 247

402 248

418 249

364 250

251

408 252

253

254

413 255

405 256

257

394 258

390 259

434 260

386 261

368 262

412 263

406 264

265

378The compounds of Examples 1-265 show an HDA enzyme IC₅₀ in the rangefrom about 0.005 to about 0.5 μM.

EXAMPLE B1

Cell lines H1299 (human lung carcinoma cell) and HCT116 (colon tumorcell) are obtained from the American Type Culture Collection, Rockville,Md. The cell lines are free of Mycoplasma contamination (Rapid DetectionSystem by Gen-Probe, Inc., San Diego, Calif.) and viral contamination(MAP testing by MA BioServices, Inc., Rockville, Md.). The cell linesare propagated and expanded in RPMI 1640 medium containing 10%heat-inactivated FBS (Life Technologies, Grand Island, N.Y.). Cellexpansions for implantation are performed in cell factories (NUNC,purchased from Fisher Scientific, Springfield, N.J.). Cells areharvested at 50-90% confluency, washed once with HBSS (Hank's BalancedSalt Solution) containing 10% FBS, and suspended in 100% HBSS.

Cell proliferation is measured with a commercial MTS kit (Promega,Madision, Wis.) assay using an adaptation of published procedures, forexample, that disclosed in Feasibility of drug screening with panels ofhuman tumor cell lines using a microculture tetrazolium assay, Alley MC, et al., Cancer Res. 1988; 48:589-601. Cells are plated in 96-welltissue culture dishes, with top and bottom rows left empty. H1299 andHCT116 cells are suspended in complete media at a density of 5.3×10³ and3.6×10³ cell/mL, respectively, and 190 μl are added per well. Each cellline is added to one half of the plate. Complete medium (200 μL) isadded to the top and bottom rows. Twenty-four hours later, 10 μl of MTSsolution is added to one of the plates to determine the activity at thetime of compound addition (T₀). The plate is incubated at 37° C. for 4hours and the OD₄₉₀ is measured on a Molecular Devices Thermomax at 490nm using the Softmax program. The To plate serves as a reference forinitial activity at the beginning of the experiment.

Five serial dilutions (1:4) of each compound are made in a 96-deep wellplate with the highest concentrations on the edge of plate. Two celllines are tested with two compounds per plate.0 Ten microliters of eachof the five dilutions are added in triplicate and complete medium aloneis added to columns six and seven. The plates are incubated at 37° C.for 72 hours. The MTS solution is added (as for the T₀ plate) and readfour hours later.

In order to analyze the data, the average background value (media alone)is subtracted from each experimental well; the triplicate values areaveraged for each compound dilution. The following formulas are used tocalculate percent growth.If X>T₀, % Growth=((X−T ₀)/(GC−T ₀))×100If X<T₀, % Growth=(X−T ₀)/T ₀)×100in which T₀=(average value of cell viability at time 0)−backgroundGC=average value of untreated cells (in triplicate)−backgroundX=average value of compound treated cells (in triplicate)−backgroundThe “% Growth” is plotted against compound concentration and used tocalculate IC₅₀s employing the linear regression techniques between datapoints to predict the concentration of compounds at 50% inhibition.

Lactate salts ofN-hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(CMD1),N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(CMD2),N-hydroxy-3-[4-[[[2-(5-methoxy-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(CMD3), N-hydroxy-3-[4-[[[2-(5-fluoro-1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide (CMD4),N-hydroxy-3-[4-[[[2-(benzofur-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(CMD5) having a purity of higher than 95% are dissolved in puredimethylsulfoxide (DMSO) to create a stock solution. The stock solutionis diluted with 5% dextrose injection, USP, just prior to dosing. Inaddition,N-(2-aminophenyl[N-pyridin-3-yl)methoxycarbonylaminomethyl]benzamide issynthesized in accordance with Example 48 of EP 0 847 992 and used as acontrol compound (CMDC). Inhibition of cell growth in monolayer for 72hours of compound treatment is measured in triplicate-experiments andused to derive the IC₅₀ by MTS assay. The results are shown in Table B1.TABLE B1 Active Monolayer Growth IC₅₀ (μM) Compound H1299 HCT116 CMD10.40 0.03 CMD2 0.15 0.01 CMD3 0.58 0.03 CMD4 0.28 0.03 CMD5 0.18 0.03CMDC 6.8 0.67The results show that the hydroxamate compounds of the present inventionare highly active in inhibition of tumor cell growth. In addition to theabove results, it has been observed that the compounds selectivelyinhibited tumor cells while showing minimal inhibition activities innon-tumorous cells.

The cells treated with the hydroxamate compounds are also tested for theinduction of p21 promoter, which is a key mediator of G1 arrest anddifferentiation. The hydroxamate compounds activate the p21 promoter toa readily detectable level at a concentration within two-fold of theirrespective IC₅₀ for monolayer cell growth inhibition in H1299. Withoutbeing bound by amy particular theory, the correlation appears todemonstrate that HDA inhibition leads to transcriptional activation ofgenes that inhibit tumor cell proliferation.

EXAMPLE B2

HDA is partially purified from H1299, human non-small cell lungcarcinoma cells (obtained from American Type Culture Collection, 12301Parklawn Drive, Rockville, Md. 20852, USA). Cells are grown to 70-80%confluence in RPMI media in the presence of 10% FCS, harvested and lysedby sonication. The lysate is centrifuged at 23,420 g for 10-15 min, thesupernatant is applied to a Hiload 26/10 High performance Q-sepharosecolumn (Amersham Pharmacia Biotech), and equilibrated with a buffercontaining 20 mM Tris pH8.0, 1 mM EDTA, 10 mM NH₄Cl₂, 1 mM WMercaptoethanol, 5% glycerol, 2 μg/mL aprotinin, 1 μg/mL leupeptin, and400 mM PMSF. Proteins are eluted in 4 mL aliquots with a linear gradientfrom 0-500 mM NaCl in the above buffer at a flow rate of 2.5 mL/min.Each preparation of partially purified HDA enzyme is titrated todetermine the optimal amount needed to obtain a signal to noise ratio ofat least 5 to 1. Generally, 20-30 μl of partially purified HDA (5-10 mgprotein/mL) is mixed with 2 μL of compound solution in DMSO in a deepwell titer plate (Beckman). The compounds are serially diluted in DMSOto generate stocks at 20-fold of the assay concentrations. Finalconcentrations of compounds in the assay are 10 μM, 2 μM, 400 nM, 80 nM,and 16 nM with the final percentage of DMSO in each enzyme reactionequaling 0.1%. Each concentration of compound is assayed in duplicate.The substrate used in the reaction is a peptide of amino acid sequence,SGRGKGGKGLGKGGAKRHRKVLRD, corresponding to the twenty-four N-terminalamino acids of human histone H4, biotinylated at the N-terminus andpenta-acetylated, at each lysine residue with ³H-acetate. To initiatethe reaction, the substrate is diluted in 10 μL of Buffer A (100 mM TrispH 8.0, 2 mM EDTA), added to the enzyme mixture and collected at thebottom of the deep well plate by centrifugation for 5 minutes at 1500rpm. Following centrifugation, the mixture is incubated at 37° C. for1.5 hr. The reaction is stopped by the addition of 20 μL of the StopBuffer (0.5N HCl, 0.08M Acetic Acid). At this point, the assay proceedsto the robotic extraction phase or is frozen for several days at −0° C.

The extraction of enzymatically cleaved ³H-acetate groups from thereaction mixture is achieved with the solvent TBME (t-butyl methylether) using the Tomtec Quadra 96 workstation. A program is written toadd 200 μL of TBME to a 96 “deep well” plate. The workstation isprogrammed to aspirate 50 μL of air followed by 200 μL of TBME andfinally another 25 μL of air, which is dispensed into the each well ofthe plate. The contents of the deep well, were mixed thoroughly bypipetting 160 μL up and down 10 times. Before addition of TBME to thereaction mixture, it is necessary to “pre-wet” the pipette tips withTBME to prevent the solvent from dripping during the transfer to thedeep well plate. The organic and aqueous phases in the deep well areseparated by centrifugation at 1500 rpm for 5 min. Opti-Phase Supermixliquid scintillation cocktail (200 μL) (Wallac) is added to each well ofthe 96-well Trilux plate (Wallac). The deep well and Trilux plates areplaced back on the workstation programmed to aspirate 25 μL of air intothe pipette tips followed by 100 μL of the upper TBME phase and transferit into the Trilux plate. The solutions are mixed by pipetting andexpelling 50 μL, five times, within the same well. The Trilux plate iscovered with clear film and read on a 1450 MicroBeta Trilux liquidscintillation and luminescence counter (Wallac) with a color/chemicalquench and dpm correction.

In order to determine the IC₅₀ values, the data are analyzed on aspreadsheet. The analysis requires a correction for the backgroundluminescence that is accomplished by subtracting the dpm values of wellswithout ³H substrate from the experimental wells. The corrected dpmvalues along with the concentrations of the compounds are used tocalculate IC₅₀ using the user-defined spline function. This functionutilizes linear regression techniques between data points to calculatethe concentration of compounds that produced 50% inhibition. The resultsare shown in Table B2. TABLE B2 Compound HDA Enzyme Activity IC₅₀ (μM)CMD1 0.032 CMD2 0.063 CMD3 0.014 CMD4 0.014 CMD5 0.016 CMDC >10

EXAMPLE B3

The A549 non-small cell lung human tumor cell line is purchased from theAmerican Type Culture Collection, Rockville, Md. The cell line is freeof Mycoplasma contamination (Rapid Detection System by Gen-Probe, Inc.,San Diego, Calif.) and viral contamination (MAP testing by MABioServices, Inc., Rockville, Md.). The cell line is propagated andexpanded in RPMI 1640 medium containing 10% heat-inactivated FBS (LifeTechnologies, Grand Island, N.Y.). Cell expansions for implantation areperformed in cell factories (NUNC, purchased from Fisher Scientific,Springfield, N.J.). Cells are harvested at 50-90% confluency, washedonce with HBSS containing 10% FBS, and suspended in 100% HBSS.

Outbred athymic (nu/nu) female mice (“Hsd:Athymic Nude-nu” from HarlanSprague Dawley, Indianapolis, Ind.) are anesthetized with Metofane(Mallinckrodt Veterinary, Inc., Mundelein, Ill.), and 100 μL of the cellsuspension containing 1×10⁷ cells is injected subcutaneously into theright axillary (lateral) region of each animal. Tumors are allowed togrow for about 20 days until a volume of 10-100 mm is achieved. At thispoint, mice bearing tumors with acceptable morphology and size aresorted into groups of eight for the study. The sorting process producesgroups balanced with respect to mean and range of tumor size. Antitumoractivity is expressed as % T/C, comparing differences in tumor volumesfor treatment group (T) to vehicle control group (C). Regressions arecalculated using the formula: (1−T/T₀)×100%, where T is the tumor volumefor the treatment group at the end of the experiment, and T₀ is thetumor volume at the beginning of the experiment.

CMD1 is administered intravenously, once daily 5×/week for three weeks,at doses of 10, 25, 50, or 100 mg/kg. The final DMSO concentration is10%. Each test group has eight mice. Tumors are measured, and individualanimal body weights recorded. Table B3 shows the results on the 41^(st)day. TABLE B3 Δ MEAN Δ % TUMOR BODY DOSE VOLUME*¹ % WEIGHT*² COMPOUND(mg/kg) (mm³ ± SEM*³) T/C (% ± SEM*³) 10% DMSO/D5W*⁴ — 376 ± 55  — +11.9± 0.2  CMD1 10 121 ± 27  32 +1.3 ± 0.3 CMD1 25 77 ± 32 20 −0.9 ± 0.3CMD1 50 57 ± 10 15 −0.4 ± 0.3 CMD1 100 28 ± 25 7 +0.4 ± 0.3Note:*¹Difference in mean tumor volume for a group of animals at the end ofthe experiment minus mean tumor volume at the beginning.*²Difference in body weight for a group of animals at the end of theexperiment minus mean tumor volume at the beginning.*³Standard error of the mean*⁴5% dextrose injection, USP.

EXAMPLE B4

Example B3 repeated except CMD2 is used. Table B4 shows the results.TABLE B4 Δ MEAN Δ % TUMOR BODY DOSE VOLUME WEIGHT COMPOUND (mg/kg) (mm³± SEM) % T/C (% ± SEM) 10% DMSO/D5W — 135 ± 43  — +6.7 ± 1.1 CMD2 25 37± 16 27 −4.2 ± 2.5 CMD2 50 29 ± 15 21 −2.9 ± 1.5

EXAMPLE B5

Example B3 is repeated except the HCT116 colon tumor cell line is usedin place of the A549 cell line. The HCT116 cell line is also obtainedfrom American Type Culture Collection, Rockville, Md., and the cell lineis free of Mycoplasma contamination and viral contamination. The resultsare recorded on the 34^(th) day and are shown in Table B5. TABLE B5 ΔMEAN TUMOR Δ % DOSE VOLUME % BODY WEIGHT COMPOUND (mg/kg) (mm³ ± SEM)T/C (% ± SEM) 10% DMSO/D5W —  759 ± 108 — −0.4 ± 0.4 CMD1  50*¹⁰ 186 ±40 25 −7.4 ± 0.8 CMD1 100   140 ± 38 18 −3.2 ± 0.4Note:*¹⁰Seven mice are tested in this group.

EXAMPLE B6

Example B4 is repeated except the HCT116 colon tumor cell line is usedin place of the A549 cell line. The HCT116 is also obtained fromAmerican Type Culture Collection, Rockville, Md., and the cell line isfree of Mycoplasma contamination and viral contamination. The resultsare recorded on the 34^(th) day and are shown in Table B6. TABLE B6 ΔMEAN TUMOR Δ % DOSE VOLUME % BODY WEIGHT COMPOUND (mg/kg) (mm³ ± SEM)T/C (% ± SEM) 10% DMSO/D5W —  759 ± 108 — −0.4 ± 0.4 CMD2 10 422 ± 75 56−10.2 ± 0.5  CMD2 25 305 ± 47 40 −7.0 ± 0.2 CMD2 50  97 ± 30 13 −7.3 ±0.3 CMD2 100 132 ± 30 17 −9.4 ± 0.4

EXAMPLE B7

Annexin V binding was used as a marker for the early stages ofapoptosis. A549, HCT116 and Normal Dermal Human Fibroblasts (NDHF) cellsare treated separately with four compounds (CMD1, CMD2, CMD3 and CMD4)for 24 or 48 hours, stained with annexin V and compared to cells treatedsimilarly with vehicle (DMSO). Cells are examined by fluorescencemicroscopy. Those undergoing apoptosis exhibit green fluorescentmembrane staining. Viability is assessed by the counterstain, propidiumiodide. Cells detected by red fluorescence are not viable. A smallpercentage of A549 and the majority of HCT116 cells exhibit cell surfacestaining with annexin V after 24 hour exposure to each of the fourcompounds. After 48 hour treatment, the majority of the A549 and HCT116stain, with annexin V and/or propidium iodide indicating that thecompounds induce apoptotic cell death. In contrast, NDHF cells do notshow noticeable annexin V staining after 24 hour exposure and limitedannexin V staining with CMD3 after 48 hour. These data show that NDHFcells predominantly underwent non-lethal growth arrest upon compoundtreatment, consistent with the cell cycle profile.

The staining results demonstrate that the hydroxamate compounds of thepresent invention cause tumor cells to die by apoptosis, while causingnormal fibroblast to predominantly undergo cell cycle arrest, clearlydemonstrating the selective efficacy of the present compounds.

1. A compound of the formula (I)

wherein R₁ is H, halo, or a straight chain C₁-C₆ alkyl; R₂ is selectedfrom H, C₁-C₁₀ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, —(CH₂)_(n)OC(O)R₆, amino acyl,HON—C(O)—CH═C(R₁)-aryl-alkyl- and —(CH₂)_(n)R₇; R₃ and R₄ are the sameor different and independently H, C₁-C₆ alkyl, acyl or acylamino, or R₃and R₄ together with the carbon to which they are bound represent C═O,C═S, or C═NR₈, or R₂ together with the nitrogen to which it is bound andR₃ together with the carbon to which it is bound can form a C₄-C₉heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromaticpolyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; R₅is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,aromatic polycycle, non-aromatic polycycle, mixed aryl and non-arylpolycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryland non-aryl polyheterocycle; n, n₁, n₂ and n₃ are the same or differentand independently selected from 0-6, when n, is 1-6, each carbon atomcan be optionally and independently substituted with R₃ and/or R₄; X andY are the same or different and independently selected from H, halo,C₁-C₄ alkyl, NO₂, C(O)R₁, OR₉, SR₉, CN, and NR₁₀R₁₁; R₆ is selected fromH, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR₁₂, andNR₁₃R₁₄; R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, andNR₁₂SO₂R₆; R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl; R₉ is selected from C₁-C₄ alkyl and C(O)-alkyl; R₁₀ andR₁₁ are the same or different and independently selected from H, C₁-C₄alkyl, and —C(O)-alkyl; R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₆ heterocycloalkylalkyl, aryl,mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, andheteroarylalkyl; R₁₃ and R₁₄ are the same or different and independentlyselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino-acyl, or R₁₃ and R₁₄together with the nitrogen to which they are bound are C₄-C₉heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromaticpolyheterocycle or mixed aryl and non-aryl polyheterocycle; R₁₅ isselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH₂)_(m)ZR₁₂; R₁₆ isselected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and(CH₂)_(m)ZR₁₂; R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl,heteroarylalkyl, polyheteroaryl and NR₁₃R₁₄; m is an integer selectedfrom 0 to 6; and Z is selected from O, NR₁₃, S and S(O); or apharmaceutically acceptable salt thereof.
 2. A compound of claim 1wherein each of R₁, X, Y, R₃, and R₄ is H.
 3. A compound of claim 2 oneof n₂ and n₃ is zero and the other is
 1. 4. A compound of claim 3wherein R₂ is H or —CH₂—CH₂—OH.
 5. A compound of claim 1 of the formula(Ia)

wherein n₄ is 0-3, R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl,C₄-C₉ heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and —(CH₂)_(n)R₇; R₅′ isheteroaryl, heteroarylalkyl, an aromatic polycycle, a non-aromaticpolycycle, a mixed aryl and non-aryl polycycle, polyheteroaryl, or amixed aryl and non-aryl polyheterocycle or a pharmaceutically acceptablesalt thereof.
 6. A compound of claim 1 of the formula (Ia)

wherein n₄ is 0-3, R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl,C₄-C₉ heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and —(CH₂)_(n)R₇; R₅′ isaryl, arylalkyl, an aromatic polycycle, a non-aromatic polycycle or amixed aryl and non-aryl polycycle, or a pharmaceutically acceptable saltthereof.
 7. A compound of claim 6 wherein R₅′ is aryl or arylalkyl.
 8. Acorm pound of claim 7 wherein R₅′ is p-fluorophenyl, p-chlorophenyl,p-O—C₁-C₄-alkylphenyl, p-C₁-C₄-alkylphenyl, benzyl, ortho, meta orpara-fluorobenzyl, ortho, meta or para-chlorobenzyl, or ortho, meta orpara- mono, di or tri-O—C₁-C₄-alkylbenzyl.
 9. A compound of claim 1 offormula Ib:

wherein R₂′ is selected from H, C₁-C₆ alkyl, C₄-C₆ cycloalkyl,alkylcycloalkyl, and —(CH₂)₂₋₄OR₂₁ where R₂₁ is H, methyl, ethyl,propyl, or isopropyl, and R₅″ is unsubstituted or substituted1H-indol-3-yl, benzofuran-3-yl or quinolin-3-yl or a pharmaceuticallyacceptable salt thereof.
 10. A compound of claim 9 wherein R₅″ issubstituted 1H-indol-3-yl or substituted benzofuran-3-yl.
 11. A compoundof claim 1 of formula (Ic)

wherein the ring containing Z₁ is aromatic or non-aromatic whichnon-aromatic rings are saturated or unsaturated, Z₁ is O, S or N—R₂₀;R₁₈ is H, halo, C₁-C₆alkyl, C₃-C₇cycloalkyl; aryl, or heteroaryl; R₂₀ isH, C₁-C₆alkyl, C₁-C₆alkyl-C₃-C₉cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, acyl or sulfonyl; A₁ is 1, 2 or 3 substituents whichare independently H, C₁-C-₆alkyl, —OR₁₉, halo, alkylamino, aminoalkyl,halo, or heteroarylalkyl, R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and—(CH₂)_(n)R₇; R₁₉ is selected from H, C₁-C₆alkyl, C₄-C₉cycloalkyl,C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;v is 0, 1 or 2, p is 0-3, and q is 1-5 and r is 0 or q is 0 and r is 1-5or a pharmaceutically acceptable salt thereof.
 12. A compound of claim11 wherein Z₁ is N—R₂₀.
 13. A compound of claim 11 wherein R₂ is H or—CH₂—CH₂—OH and the sum of q and r is
 1. 14. A compound of claim 1 ofthe formula (Id)

wherein Z₁ is O, S or N—R₂₀, R18 is H, halo, C₁-C₆alkyl,C₃-C₇cycloalkyl, unsubstituted phenyl, substituted phenyl, orheteroaryl, R₂₀ is H, C₁-C₆alkyl, C₁-C₆alkyl-C₃-C₉cycloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, acyl or sulfonyl; A₁ is 1, 2 or3 substituents which are independently H, C_(1-C-) ₆alkyl, —OR₁₉, orhalo, R₁₉ is selected from H, C₁-C₆alkyl, C₄-C₉cycloalkyl,C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and—(CH₂CH═CH(CH₃)(CH₂))₁₋₃H; p is 0-3, and q is 1-5 and r is 0 or q is 0and r is 1-5, or a pharmaceutically acceptable salt thereof.
 15. Acompound of claim 14 wherein R₂ is H or —CH₂—CH₂—OH and the sum of q andr is
 1. 16. A compound of claim 11 of formula (Ie)

or a pharmaceutically acceptable salt thereof.
 17. A compound of claim16 wherein R₁₈ is H, fluoro, chloro, bromo, a C₁-C₄alkyl group, aC₃-C₇cycloalkyl group, phenyl or a heteroaryl ring.
 18. A compound ofclaim 16 wherein R₂ is H, or —(CH₂)_(s)CH₂OH and wherein s is 1-3.
 19. Acompound of claim 18 wherein R₁ is H and X and Y are each H, and whereinq is 1-3 and r is 0 or wherein q is 0 and r is 1-3.
 20. A compound ofclaim 16 wherein R₁₈ is H, methyl, ethyl, t-butyl, trifluoromethyl,cyclohexyl, phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-furanyl,2-thiophenyl, or 2-, 3- or 4-pyridyl.
 21. A compound of claim 20 whereinR₂ is H, or —(CH₂)_(s)CH₂OH and wherein s is 1-3.
 22. A compound ofclaim 21 wherein p is 1-3
 23. A compound of claim 22; wherein R₁ is Hand X and Y are each H, and wherein q is 1-3 and r is 0 or wherein q is0 and r is 1-3.
 24. A compound of claim 23 wherein R₂ is H or—CH₂—CH₂—OH and the sum of q and r is
 1. 25. A compound of claim 16wherein R₂₀ is H or C₁-C₆alkyl.
 26. A compound of claim 16 selected fromthe group consisting ofN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideandN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof.
 27. A compound of claim 1of the formula (If)

or a pharmaceutically acceptable salt thereof.
 28. A compound of claim27 wherein R₂ is H or —(CH₂)_(p)CH₂OH and p is 1-3.
 29. A compound ofclaim 28 wherein R₁ is H and X and Y are each H, and wherein q is 1-3and r is 0 or wherein q is 0 and r is 1-3.
 30. A compound of claim 29wherein R₂ is H or —CH₂—CH₂—OH and the sum of q and r is
 1. 31. Acompound of claim 27 which isN-hydroxy-3-[4-[[[2-(benzofur-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof.
 32. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof formula (I)

wherein R₁ is H, halo, or a straight chain C₁-C₆ alkyl; R₂ is selectedfrom H, C₁-C₁₀ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,C₄-C₉-heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, —(CH₂)_(n)C(O)R₆, —(CH₂)_(n)OC(O)R₆, aminoacyl, HON—C(O)—CH═C(R₁)-aryl-alkyl- and —(CH₂)_(n)R₇; R₃ and R₄ are thesame or different and independently H, C₁-C₆ alkyl, acyl or acylamino,or R₃ and R₄ together with the carbon to which they are bound representC═O, C═S, or C═NR₈, or, R₂ together with the nitrogen to which it isbound and R₃ together with the carbon to which it is bound can form aC₄-C₉ heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromaticpolyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; R₅is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,aromatic polycycle, non-aromatic polycycle, mixed aryl and non-arylpolycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryland non-aryl polyheterocycle; n, n₁, n₂ and n₃ are the same or differentand independently selected from 0-6, when n, is 1-6, each carbon atomcan be optionally and independently substituted with R₃ and/or R₄; X andY are the same or different and independently selected from H, halo,C₁-C₄ alkyl, NO₂, C(O)R₁, OR₉, SR₉, CN, and NR₁₀R₁₁; R₆ is selected fromH, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR₁₂, andNR₁₃R₁₄; R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, andNR₁₂SO₂R₆; R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl; R₉ is selected from C₁-C₄ alkyl and C(O)-alkyl; R₁₀ andR₁₁ are the same or different and independently selected from H, C₁-C₄alkyl, and —C(O)alkyl; R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, aryl,mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, andheteroarylalkyl; R₁₃ and R₁₄ are the same or different and independentlyselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R₁₃ and R₁₄together with the nitrogen to which they are bound are C₄-C₉heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromaticpolyheterocycle or mixed aryl and non-aryl polyheterocycle; R₁₅ isselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH₂)_(m)ZR₁₂; R₁₆ isselected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and(CH₂)_(m)ZR₁₂; R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl,heteroarylalkyl, polyheteroaryl and NR₁₃R₁₄; m is an integer selectedfrom 0 to 6; and Z is selected from O, NR₁₃, S and S(O); or apharmaceutically acceptable salt thereof.
 33. A pharmaceuticalcomposition of claim 32 wherein the compound of formula (I) is selectedfrom the group consisting of selectedN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideandN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof.
 34. A pharmaceuticalcomposition of claim 32 which isN-hydroxy-3-[4-[[[2-(benzofur-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof.
 35. A method for treatinga proliferative disorder in a mammal which comprises administering tosaid mammal a compound of the formula (I)

wherein R₁ is H, halo, or a straight chain C₁-C₆ alkyl; R₂ is selectedfrom H, C₁-C₁₀ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, —(CH₂)_(n)OC(O)R₆, amino acyl,HON—C(O)—CH═C(R₁)-aryl-alkyl- and —(CH₂)_(n)R₇; R₃ and R₄ are the sameor different and independently H, C₁-C₆ alkyl, acyl or acylamino, or R₃and R₄ together with the carbon to which they are bound represent C═O,C═S, or C═NR, or R₂ together with the nitrogen to which it is bound andR₃ together with the carbon to which it is bound can form a C₄-C₉heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromaticpolyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; R₅is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,aromatic polycycle, non-aromatic polycycle, mixed aryl and non-arylpolycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryland non-aryl polyheterocycle; n, n₁, n₂ and n₃ are the same or differentand independently selected from 0-6, when n₁ is 1-6, each carbon atomcan be optionally and independently substituted with R₃ and/or R₄; X andY are the same or different and independently selected from H, halo,C₁-C₄ alkyl, NO₂, C(O)R₁, OR₉, SR₉, CN, and NR₁₀R₁₁; R₆ is selected fromH, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR₁₂, andNR₁₃R₁₄; R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, andNR₁₂SO₂R₆; R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl; R₉ is selected from C₁-C₄ alkyl and C(O)-alkyl; R₁₀ andR₁₁, are the same or different and independently selected from H, C₁-C₄alkyl, and —C(O)-alkyl; R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, aryl,mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, andheteroarylalkyl; R₁₃ and R₁₄ are the same or different and independentlyselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R₁₃ and R₁₄together with the nitrogen to which they are bound are C₄-C₉heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromaticpolyheterocycle or mixed aryl and non-aryl polyheterocycle; R₁₅ isselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH₂)_(m)ZR₁₂; R₁₆ isselected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and(CH₂)_(m)ZR₁₂; R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl,heteroarylalkyl, polyheteroaryl and NR₁₃R₁₄; m is an integer selectedfrom 0 to 6; and Z is selected from O, NR₁₃, S and S(O); or apharmaceutically acceptable salt thereof.
 36. A method of claim 35wherein the compound of formula (I) is selected from the groupconsisting ofN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideandN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof.
 37. A method forregulating p21 promoter which comprises introducing a compound of theformula (I)

wherein R₁ is H, halo, or a straight chain C₁-C₆ alkyl; R₂ is selectedfrom H, C₁-C₁₀ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, —(CH₂)_(n)OC(O)RN, amino acyl,HON—C(O)—CH═C(R₁)-aryl-alkyl- and —(CH₂)_(n)R₇; R₃ and R₄ are the sameor different and independently H, C₁-C₆ alkyl, acyl or acylamino, or R₃and R₄ together with the carbon to which they are bound represent C═O,C═S, or C═NR₈, or R₂ together with the nitrogen to which it is bound andR₃ together with the carbon to which it is bound can form a C₄-C₉heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromaticpolyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; R₅is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,aromatic polycycle, non-aromatic polycycle, mixed aryl and non-arylpolycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryland non-aryl polyheterocycle; n, n₁, n₂ and n₃ are the same or differentand independently selected from 0-6, when n₁ is 1-6, each carbon atomcan be optionally and independently substituted with R₃ and/or R₄; X andY are the same or different and independently selected from H, halo,C₁-C₄ alkyl, NO₂, C(O)R₁, OR₉, SR₉, CN, and NR₁₀R₁₁; R₆ is selected fromH, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR₁₂, andNR₁₃R₁₄; R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, andNR₁₂SO₂R₆; R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl; R₉ is selected from C₁-C₄ alkyl and C(O)-alkyl; R₁₀ andR₁₁ are the same or different and independently selected from H, C₁-C₄alkyl, and —C(O)-alkyl; R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, aryl,mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, andheteroarylalkyl; R₁₃ and R₁₄ are the same or different and independentlyselected from H, C₁-C₆, alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R₁₃ and R₁₄together with the nitrogen to which they are bound are C₄-C₉heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromaticpolyheterocycle or mixed aryl and non-aryl polyheterocycle; R₁₅ isselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH₂)_(m)ZR₁₂; R₁₆ isselected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and(CH₂)_(m)ZR₁₂; R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl,heteroarylalkyl, polyheteroaryl and NR₁₃R₁₄; m is an integer selectedfrom 0 to 6; and Z is selected from O, NR₁₃, S and S(O); or apharmaceutically acceptable salt thereof, into the environment of amammalian cell.
 38. A method of claim 37 wherein the compound of formula(I) is selected from the group consisting ofN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-r[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideandN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof.